Process for the preparation of (pyridinylidene)-phthalides

ABSTRACT

A process for the preparation of (pyridinylidene)-phthalides starting from 3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids and pyridinecarbaldehydes, is described.

This APPLN is A 371 of PCT/EP01/01244 filed Jun. 28, 2001

FIELD OF THE INVENTION

The present invention relates to a process for the preparation of(pyridinylidene)-phthalides and, more particularly, relates to a processfor preparing (pyridinylidene)-phthalides starting from3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids andpyridinecarbaldehydes. The (pyridinylidene)-phthalides are knowncompounds, described in the literature.

In the International patent applications WO 98/35958 in the name ofNovartis and WO 00/05218 in the name of the same applicant various(pyridinylidene)-phthalides are used as useful intermediates forpreparing phthalazines endowed with inhibitory activity of angiogenesisand PDE4 enzyme respectively.

BACKGROUND OF INVENTION

Several methods for synthesizing arylidenephthalides are known and someof them, particularly, have been employed for preparing(pyridinylidene)-phthalides.

For instance J. Ploquin et al. In J. Het. Chem. (1980), 17, 961 reportthe preparation of (pyridinylidene)-phthalides by hot condensationbetween phthalic anhydride and methyl-pyridines. This reaction, however,has a poor applicative interest because, besides presenting poor yields,it is limited to obtain unsubstituted or symmetrically substituted onthe phthalic ring derivatives. In fact an asymmetrical substitutionwould inevitably lead to the formation of regioisomers difficult toseparate.

A different process for preparing, inter alia,(pyridinylidene)-phthalides also asymmetrically substituted, reported inthe already cited patent application WO 00/05218, is based on the Wittigcondensation between a phosphonium salt XI and an aldehyde XII as heredepicted:

wherein A also represents pyridine and Z′ can be absent.

Nevertheless this process, although it has a pratically quantitativeyield, presents a series of disadvantages that make it of poorindustrial interest.

In fact the preparation of the phosphonium salt XI, that occursaccording to the following schema:

shows some critical points. Particularly the radicalic bromurationreaction of XI is strongly esothermic, the resultant bromurated productX is unstable and therefore it must be quickly used in the reaction withtriphenylphosphine to give the phosphonium salt XI.

Lastly during this last step the molecular weight of the substrateincreases considerably involving an undesired increase of the reactionmass. Besides, in the subsequent Wittig reaction the formation ofequimolar quantities of phosphineoxide occurs that ulteriorlycomplicates the synthetic feasibility.

All these problems make the above mentioned process hardly practicableat industrial level. Among the known alternative methods for preparingarylidenephthalides it is of particular interest the one described by R.H. Pager et al. in Tetrahedron, (1984), 40, 1517 that uses differentlysubstituted benzaldehydes (4) and3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid (1) as startingproducts.

In all the examined cases the reaction, performed directly by heatingthe mixture of the reagents, leads to the formation of mixtures of3-arylidene-phthalides (3) and 3-(arylhydroxymethyl)-phthalides (2) invariable ratios, with overall yields from 47 to 90%.

The authors study the course of the above reporteddecarboxylation-condensation reaction by varying some experimentalparameters, such as the type and the quantity of aldehyde, the solventabsence or presence, the reaction time and temperature.

Regarding the influence exerted by the substituents of the aldehyde (4)upon the course of the reaction the authors declare that “only in thecase of electrondonor groups merely the dehydration product (3) isobtained “ (see lines 24, 1^(st) column, page 1519).

Besides, it seems that the reaction is advantageous only if it isperformed without a solvent while it results clearly disadvantageous ifit is performed in its presence. In particular in apolar solvents a 140°C. it doesn't occur, while in the case of polar solvents, such as e.g.dimethylsulfoxide, it exclusively leads to obtain the alcohol (2) withpoor fields and only with relevant excesses (2-6 equivalents) ofaldehyde (see from line 19 forward, 1^(st) column, pag. 1519). Moreoverthe dehydation of (2) to (3) doesn't occur appreciably in this solvent.Therefore from the work presented by Rolf H. Prager et al. it may beconcluded that in order to obtain directly the compounds of formula (3)with significant yields the above mentioned reaction should be performedstarting from electron-rich aldehydes (4) by heating in the absence of asolvent.

On the contrary we have surprisingly found that also using electron-pooraldehydes such as the pyridinecarbaldehydes, even in almoststechiometric ratio it is possible to obtain directly the correspondingarylidenephthalides with high yields if the reaction is performed in thepresence of anhydrides.

With reference to this it has been hypothesized that the anhydride,besides probably acting as a dehydrator, is directly involved in theinitial activation of the carboxylic function of the3-oxo-1,3-dihydro-isobenzofuran-1-carboxylic acids.

BRIEF SUMMARY

Therefore object of the present invention is a process for preparingpyridinylidene-phthalides of formula

wherein

Py represents a 2, 3 or 4-pyridinyl group optionally substituted by oneor more substituents selected from halogen, nitro, cyano, oxo andcarboxy groups;

R and R₁, which may be the same or different, represent hydrogen, C₁-C₆alkyl or a group OR₂ wherein R₂ represents a linear or branched C₁-C₆alkyl, a C₄-C₇ cycloalkyl or a C₁-C₆ polyfluoroalkyl;

The bond indicates both the isomers E and Z;

by reaction of a compound of formula

wherein R and R₁ have the above reported meanings;

with an aldehyde of formula

Py-CHO   (III)

wherein Py has the above reported meaning;

by heating the mixture of the compounds having formula II and III in thepresence of an anhydride and optionally in admixture with a suitablesolvent.

DETAILED DESCRIPTION OF THE INVENTION

The process object of the present invention can be easily performed andit allows to obtain pyridinylidene-phthalides of formula I with goodyields without using the aforesaid phosphonium salt XI.

The process object of the present invention provides for the reactionbetween a compound of formula II and a compound of formula III.

The compounds of formula II are known and easily obtainable for instanceaccording to the synthetic route described in J. Chem. Soc. (1929), 200.

In the compounds of formula II the groups R and R₁ have the abovereported meanings.

Particularly preferred compounds of formula II are those wherein atleast one between R and R₁ represents OR₂, even more preferred thosewherein one or both between R and R₁ are OCH₃.

Also the starting compounds of formula III are generally known,commercially available or obtainable according to processes reported inthe literature.

Particularly preferred compounds of formula III are those wherein Pyrepresents a 4-pyridinyl group, even more preferred if Py represents adihalosubstituted 4-pyridinyl residue. In the process object of thepresent invention the compounds of formula III are generally used withrespect to the compounds of formula II in a molar ratio from 0.5 to 4.Preferably they are used in a ratio from 0.8 to 1.5, even morepreferably from 0.9 to 1.1.

The present process is performed in the presence of an anhydride.

The term “anhydride” means a reagent selected in the group of theorganic or inorganic anhydrides, respectively derived from organic orinorganic acids, or mixed, including in this class also the acyl, alkyland arylsulfonyl halides.

Examples of anhydrides utilizable in the present process are, in thecase of the organic anhydrides, acetic, trifluoroacetic, ortrifluoromethansulfonic anhydride, in the case of inorganic anhydrides,phosphoric or sulphuric anhydride or thionylchloride, while among themixed anhydrides, acetyl, tosyl or mesyl chloride, these acyl chloridesbeing consider herewith as anhydrides of an organic acid and hydrogenchloride.

This, for example, acetyl chloride is the mixed anhydride of acetic acidand hydrogen chloride.

The organic anhydrides are particularly preferred.

For practical reasons acetic anhydride is preferably used.

In the process object of the present invention the above cited anhydridecan be employed in a large excess as regards the starting compound offormula n acting also as solvent, for example in a molar ratio of 10:1as regards the compound of formula II.

Alternatively the anhydride can be used as regards the compound III in anarrower molar ratio, for example from 1 to 3. In that case the reactionmay request the presence of an appropriate co-solvent.

In this connection examples of usable solvents are high boiling apolarsolvents such as for example the aromatic hydrocarbons, optionallychlorosubstituted.

Preferred aromatic solvents are toluene, xylene and chlorobenzene,particularly preferred is toluene.

For practical reasons the process object of the present invention ispreferably performed in an excess of acetic anhydride.

Also the usage of other activating systems, such as for example theLewis acids, or dehydrators, such as the distillation of appropriateazeotropic mixtures, falls, moreover, within the scope of the presentinvention as an alternative to the anhydride.

The present process is performed by heating the mixture of the compoundsof formula II and III, in the presence of the anhydride and optionallyof the appropriate solvent.

Preferably the reaction mixture is heated at the reflux temperature.

The process object of the present invention allows to obtain a final rawproduct essentially constituted by the mixture E/Z of the compounds offomula I, usable directly without further treatment of purification.

The compounds of formula I, prepared according to the process object ofthe present invention, can for example be directly used in the synthesisof PDE4 inhibitors having a phthalazinic structure, as described in thealready cited International application WO 00/05218.

Said compounds have the formula

wherein

R, R₁ and Py have the above reported meanings;

is a single or double bond;

Y represents two hydrogen atoms or a group ═O when is a single bond, orwhen is a double bond Y is hydrogen cyano, (C₁-C₄)-alkoxycarbonyl,amido, optionally sustituted aryl or heterocyclyl, (C₁-C₈)-alkyl,(C₁-C₈)-cyclylamino;

W is absent when is a double bond or, when is a single bond, itrepresents

a) hydrogen;

b) (C₁-C₆)-alkyl optionally substituted by aryl, heterocyclyl or by agroup COR₅ wherein R₅ is hydroxy, (C₁-C₄)-alkoxy or hydroxyamino:

c) —COR₆ wherein R₆ is hydrogen, aryl, aryl-(C₁-C₆)-alkyl, optionallyalkylated or monohydroxylated amino, hydroxy, (C₁-C₄)-alkoxy, carboxy,(C₁-C₄)-alkoxycarbonyl,

or (C₁-C₄)-alkyl optionally substituted by a heterocycle;

d) (C₁-C₄)-alkylsulfonyl.

The present process is preferably applied to the synthesis of4-pyridinyl derivatives, even more preferably to the synthesis ofdihalo-substituted 4-pyridinyl derivatives. The application of thepresent process to the synthesis of3-[(3,5-dichloro-4-pyridinyl)methylene]-6-methoxy-1-(3H)-isobenzofuranoneis particularly preferred.

In a preferred embodiment of the process object of the presentinvention, the mixture of the compound II, the compound III and theanhydride is refluxed until the reaction is complete. The mixture isevaporated and the residue, recovered with the appropriate solvent andrievaporated up to dryness, can be directly used in the following step.

The process object of the present invention is advantageous chiefly forthe simplicity of realization and therefore it is particularly suitablefor the industrial application.

It allows to prepare the compounds of formula I with high yields and ina short time without using the above mentioned phosphonium salt XI,avoiding therefore the relative problems, such as for example theformation of unstable bromurated intermediates through exothermicreactions, the considerable increase of molecular weight and theformation of phosphineoxides.

A further reason of interest is the obtainment of a raw product usabledirectly in the subsequent reaction without requesting furtherpurifications.

Besides, as regards the already cited synthetic process reported in theInternational application WO 00/05218, the present process allows toreduce the total number of steps starting from the same benzoic acidderivative precursor.

With the aim to better illustrate the present invention the followingexamples are now given.

EXAMPLE 1

Preparation of3-[(3,5dichloro4-pyridinyl)methylene]-6-methoxy-1-(3H)-isobenzo-furanone

The mixture prepared at room temperature of5-methoxy-3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid (12.4 g; 0.06moles), prepared as described in J Chem. Soc. (1929), 200, and3,5-dichloro-4-pyridinecarbaldehyde (10.8 g; 0.061 moles), preparedaccording to Heterocycles (1995), 41, 675, in acetic anhydride (60 ml)was refluxed, under stirring, for 30 minutes.

The reaction was evaporated under vacuum, collected with toluene (50 ml)and evaporated again. This treatment was repeated for other two timesobtaining the desired compound (19.3 g; quantitative yield) as a yellowsolid.

¹H—NMR (200 MHz, CDCl₃) δ (ppm): 8.60 and 8.50 (s, 2H, Py); 7.77-6.20(m, 4H, Ar and CH); 3.90 and 3.80 (s, 3H, OMe); isomeric ratio 9:1.

EXAMPLE 2

Preparation of4-[(3,-dichloro-4-pyridinyl)methyl]-1,2-dihydro-7-methoxy-1-phthalazinone

In a 4 liter reactor at room temperature3-[(3,5-dichloro-4-pyridinyl)methylene]-6-methoxy-1-(3H)-isobenzofuranone(335 g; 1.04 moles), prepared as described in the example 1, andmethanol (1785 ml) were charged. Then acetic acid (178 ml) and,maintaining the temperature under 40° C. by external cooling, hydrazinemonohydrate (171.7 ml) were added by dripping.

The reaction mixture became a solution, then a new precipitate began toform. The mixture was refluxed for 2 hours. The end of the reaction waschecked by TLC (a sample was drawn and diluted with CH₂Cl₂, elutanthexane:ethylacetate=7:3). When the reaction ended, the mixture wascooled at 0° C. and filtered. The filtrate was washed with methanol (215ml). The solid was dried under vacuum at 40° C. obtaining the desiredcompound (328.5 g; yield 99%) as a light yellow solid.

EXAMPLE 3

Preparation of3-[(3,5-dichloro-4-pyridinyl)methylen]-6-methoxy-1-(3H)-isobenzofuranone

A mixture of 5-methoxy-3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid(5 g; 24 mmoles) and 3,5dichloro-4-pyridinecarboxaldehyde (4.3 g; 24mmoles) in toluene (32.5 ml) and acetic anhydride (7.5 ml) was refluxed,under stirring, for 8 hours.

The mixture was cooled at 0° C. and filtered. The filtrate was washedwith hexane.

The desired compound was obtained (5.6 g) as yellow solid.

Yield 73%

¹H—NMR in conformity with that reported in Example 1.

The same reaction was performed with 4.5 ml, 5 ml and 10 ml of aceticanhydirde. In all cases the yields were comparable. The reaction timewas inversely proportioned to the acetic anhydride concentration.

EXAMPLE 4

Preparation of3-[(3-chloro-4-pyridinyl)methylen]-6-methoxy-1-(3H)-isobenzofuranone

A mixture of 5-methoxy-3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid(0.7 g; 3.4 mmoles) and 3-chloro-4-pyridinecarboxaldehyde (0.52 g; 3.7mmoles), prepared as described in J. Organometallic Chem. (1981), 216,139, in toluene (5 ml) and acetic anhydride (1 ml) was refluxed, understirring, for 10 hours.

The mixture was cooled at 0° C. and filtered. The filtrate was washedwith hexane.

The compound3-[(3-chloro-4-pyridinyl)methylen]-6-methoxy-1-(3H)-isobenzofuranone wasobtained (680 mg) as yellow solid.

Yield 70%

¹H—NMR (200 MHz, CDCl₃) δ (ppm): 8.58 (s 1H ClC═CH—N); 8.47 (d, 1H,JHH=5.3 Hz, N—*CH═CH), 8.11 (d, 1H, N—CH═*CH); 7.74 (d, 1H, JHH=8.5 Hz,*CH═CH—OMe); 7.35-7.28 (m, 2H, Ar); 6.61 (s, 1H, *CH-Py); 3.90 (s, 3H,CH₃—O).

EXAMPLE 5

Preparation of3-[(3,5dichloro-4-pyridinyl)methylen]-6-methoxy-1(3H)-isobenzofuranone

By following the same procedure as in Example 4 but by usingtrifluoroacetic anhydride instead of acetic anhydride, starting from5-methoxy-3-oxo-1,3-dihydro-1-isobenzofurancarboxylic acid (100 mg) thedesidered compound (109 mg) was obtained.

Yield 70%

¹H—NMR in conformity with that reported in Example 1.

What is claimed is:
 1. A process for the preparation ofpyridinylidene-phthalides of formula

wherein Py represents a 2, 3 or 4-pyridinyl group optionally substitutedby one or more substituents selected from halogen nitro, cyano, oxo andcarboxy; R and R₁, which can be the same or different between them,represent hydrogen, C₁-C₆ alkyl or a group OR₂ wherein R₂ represents alinear or branched C₁-C₆ alkyl, a C₄-C₇ cycloalkyl or a C₁-C₆polyfluoroalkyl; The bond indicates both the isomers E and Z: whichcomprises the reaction of a compound of formula

wherein R and R₁ have the meanings above reported; with an aldehyde offormula Py-CHO   (III) wherein Py has the above reported meaning; byheating of the mixture of the compounds of formula II and III in thepresence of an anhydride and optionally in admixture with a suitablesolvent.
 2. The process according to claim 1 wherein Py represents adihalosubstituted 4-pyridinyl group.
 3. The process according to claim 2wherein Py represents a 3,5-dichloro-4-pyridinyl group.
 4. The processaccording to claim 1 wherein one or both between R and R₁ representOCH₃.
 5. The process according to claim 1 wherein the compounds offormula III are employed with respect to the compounds of formula II ina molar ratio from 0.5 to
 4. 6. The process according to claim 5 whereinthe compounds of formula III are employed with respect to the compoundsof formula II in a molar ratio from 0.8 to 1.5.
 7. The process accordingto claim 6 wherein the compounds of formula III are employed withrespect to the compounds of formula II in a molar ratio from 0.9 to 1.1.8. The process according to claim 1 wherein the anhydride is an organicanhydride.
 9. The process according to claim 8 wherein the anhydride isacetic anhydride.
 10. The process according to claim 1 wherein theanhydride is used in excess.